Cells are continually faced with the decision of whether to live or die in the context of development, homeostasis, stress, and injury. Ultimately, the cell's response is strongly influenced by protein interactions of the B-cell lymphoma 2 (BCL-2) family. Deregulation of these proteins can result in inappropriate cellular persistence or premature cell death, leading to a variety of diseases, such as cancer and neurodegenerative disorders, respectively. Since the initial discovery of BCL-2, numerous homologues have been identified that together form an intricate signaling network that regulates apoptosis. Family members are defined by the presence of at least one BCL-2 homology domain (BH1-4), and are classified as multidomain anti-apoptotic, multidomain pro-apoptotic, or BH3-only pro-apoptotic proteins (Youle et al., Nature Reviews Mol. Cell Biol. 9:47-59, 2008). The BH3-only proteins are death sentinels that transmit signals of cellular stress to multidomain members (Kuwana et al., Mol. Cell 17:525-535, 2005). The anti-apoptotic proteins can bind and sequester the BH3-only and multidomain pro-apoptotic proteins to block apoptosis (Sedlak et al., Proc. Natl. Acad. Sci. U.S.A. 92:7834-7838, 1995). However, sustained cell stress can overcome the anti-apoptotic reserve, leading to activation of a multidomain pro-apoptotic protein BCL-2-associated X protein (BAX), which forms toxic pores in the outer mitochondrial membrane (OMM) and releases cytochrome c and other apoptogenic factors (Chipuk et al., Trends Cell. Biol. 18:157-164, 2008; Dejean et al., Mol. Biol. Cell. 16:2424-2432, 2005; and Jürgensmeier et al., Proc. Natl. Acad. Sci. U.S.A. 95:4997-5002, 1998). Upon initiation of apoptosis by death signals or cytotoxic stress, cytosolic BAX is triggered to undergo a major conformational change, leading to translocation to the mitochondria and formation of oligomeric pores (Wolter et al., J. Cell Biol. 139:1281-1292, 1997; Nechushtan et al., EMBO J. 18:2330-2341, 1999; Gavathiotis et al., Nature 455:1076-1081, 2008; and Gavathiotis et al., Molecular Cell 40:481-492, 2010), which triggers apoptosis of the cell.